Involvement of substance P in the anti-inflammatory effects of the peripherally selective κ-opioid asimadoline and the NK1 antagonist GR205171
Involvement of substance P in the anti-inflammatory effects of the peripherally selective κ-opioid asimadoline and the NK1 antagonist GR205171
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DOI：
10.1046/j.1460-9568.1999.00625.x
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发表时间：
1999-06-01
影响因子：
3.4
通讯作者：
Walker, JS
中科院分区：
文献类型：
--
作者：
Binder, W;Scott, C;Walker, JS
我们以前已经表明，κ-阿片类药物具有抗关节炎的特性。在这项研究中，使用两种不同的作用药物（外周选择性κ-激动剂，asimadoline，和NK 1-拮抗剂，GR 205171），我们已经研究了可能的作用的神经肽物质P（SP）在大鼠实验性关节炎的发病机制和维护。比较各组药物的抗炎作用及时间依赖性，并测定关节组织中SP的浓度。在未治疗的动物中，踝关节组织中的SP水平在疾病后期（到第21天）增加，但大大落后于临床疾病的发展。长期（第1-21天或第12-18天）但非早期短期（第1-3天）用NK 1拮抗剂GR 205171（1 mg/kg/天i. p.）显著减弱关节损伤; SP水平在21天治疗期间显示多相剂量依赖性。这些数据表明，GR 205171拮抗SP的作用，突触前以及突触后机制。用阿西马多林（5 mg/kg/天i. p.）在所有三个时间方案中产生了疾病的显著（和持续）衰减。阿司马多林对SP水平的影响是时间依赖性的：3天后SP含量降低，但在12或21天治疗后增加，矛盾的是，在每种情况下的临床改善。药物诱导的SP含量变化可能来自神经细胞或免疫细胞释放或合成的变化。结果表明，这两种药物在炎症性关节疾病的不同阶段都有潜在的治疗价值。
We have previously shown that kappa-opioids have antiarthritic properties. In this study, using two differently acting drugs (the peripherally selective kappa-agonist, asimadoline, and the NK1-antagonist, GR205171), we have examined possible roles of the neuropeptide substance P (SP) in the pathogenesis and maintenance of experimental arthritis in rats. The anti-inflammatory actions and the time dependence of these drugs were compared, and concentrations of SP determined in joint tissue. In untreated animals, SP levels in ankle joint tissue increased late in the disease (by day 21) but substantially lagged behind development of clinical disease. Prolonged (days 1-21 or days 12-18) but not early, short-term (days 1-3) treatment with the NK1-antagonist GR205171 (1 mg/kg/day i.p.) significantly attenuated joint damage; SP levels showed multiphasic dose dependence over the 21-day treatment. The data suggest that GR205171 antagonizes the action of SP by presynaptic as well as postsynaptic mechanisms. Treatment with asimadoline (5 mg/kg/day i.p.) produced marked (and sustained) attenuation of the disease with all three time regimes. The effect of asimadoline on SP levels was time dependent: reduction of SP content after 3 days but an increase after 12 or 21 days treatment, paradoxically with clinical improvement in each case. Drug-induced changes in SP content could follow from changed release or synthesis from either neural or immune cells. The results suggest that both drugs have potential therapeutic value at different stages of inflammatory joint disease.